Monoalkyl ethers of hexestrol and method of producing same



Patented Sept 1945.

UNITED STATES PATENT OFFICE MONOALKYL ETHERS OF HEXESTROL AND METHOD OF PRODUCING SAME N Drawing. Application September 26, 1941, Serial No. 412,425

2 Claims.

This invention relates to novel synthetic estrogenic products which are derivatives of hexestrol and to an improved method of making same. More particularb', the present application is directed to the discovery of the estrogenic potency of the mono-substituted ethers of 3,4 di-parahydroxyphenyl hexane, which is known in the literature under the short name of hexestrol.

In application Serial No. 375,446, filed January 22, 1941, for medicinal composition and method oi. making same, there is disclosed a novel process for preparing monoalkyl ethers of phenols of the type oi monomethylstilboestrol, which compounds were originally disclosed and claimed in the copending application of E. E. Reid, Ser. No. 342,267, flied June 25, 1940, for Medicinal composition.

It has now been found that this novel process can be applied with excellent results to the preparation oi monoalkyl ethers of 3,4,di-parahydroxyphenyl hexane (hexestrol), which exhibit an improved estrogenic quality, characterized by the production or estrus oi increased duration, when administered in doses larger than the mini mum physiological dose.

The present invention also includes as features 01' novelty the monoalkyl ethers of hexestrol, as prepared by the novel method 0! making such .ethers and of medicinal products containing ula n n i i os l l JiHI The new alkylated ethers forming the basis of the present disclosure can be represented by the type formula:

1H; wheroinnisanilkiloraralkyl roupoiany suitable structural configuration. This substituent group may be a primary or secondary, a cyclic, or a branched chain, and may include One or more unsaturated linkages.

These monoalkyl ethers of hexestrol can be produced in the following manner, and this method, disclosed in the parent application, above identified, has been found to give improved results generally in the monoalkylation oi poly-phenols, as will appear more in detail hereinafter. Considering the method as applied to monoaliql ethers of hexestrol, a suitable process may be carried out as follows:

Hexestrol, i, e., 3,4 di-parahydroxyphenyl hexane, together with an alkyl halide, and alcoholic alkali, are mixed, in such proportions that the alkali is present in an amount about 5% less than one equivalent, calculated upon the hexestrol, and the alkyl halide is present in excess, this excess being large when using low boiling alkyl halides, such as methyl iodide, where approximately two equivalents constitute a suitable amount, whereas with higher boiling halides a 10% excess is sufficient. The .three compounds in the recited admixture are held at an elevated temperature of the order or 37.5 to C., depending upon the boiling point of the alkyl halide used, for a period of twelve to forty-eight hours, depending upon the temperature used. Under the conditions of the reaction monoalkylatlon of the hexestrol present takes place during this time to a much larger degree than dialkylation. Upon completion or the reaction, as determined by the disappearance of free alkali, the mixture containing the reaction products is precipitated by the addition of water and sufllcient dilute acid to render the mixture acid in reaction, filtered, and the residue thoroughly extracted with aqueous alkali to remove any unreacted hexestrol. The washed residue is then thoroughly extracted with V; normal alkali dissolved in 40% to 45% alcohol, in which solvent mixture only the monoalkylated hexestrol is soluble. and a small amount of dialkyiated hexestrol is left behind as a by-product. The dissolved monoalkyl ether or hexestrol is then precipitated with acid, filtered on and then recrystallized from aqueous acetone or aqueous alcohol wherein any traces of residual dialkylated hexestrol are insoluble. The monoalkyl product is further recrystallized from petroleum ether until the desired purity has been reached as indicated by a constant melting point and concordant analyses.

The compositions used in making typical prod- The monoalkyl ethers of the present invention may be identified and tested chemically and physiologically in an well known manner, details of such tests being given in the Reid application ucts of the invention, together with the condi- 5 above referred to.

tions of reaction, yields, and properties of the end It will be understood that the details given are products are given in the following table: for the purpose of illustration, not description,

Alkyl ether Methyl n-Butyl n-Amyi Hexestrol 2.0 grams 1.3 grams. 1.3 grams.

Potassium hydroxide .95 equivalent .95 equivalent. .95 equivalent.

We 1' 18cc 60c 6 cc. 7cc. (abs).

Temperature 6580 Time 12 hours Yield di(crude) 5-15 5-15 Yield mono (crude) 60-80% M. P. mono-ether 100.5" M. P. di-ether 107 5 88 5 144 I Oestrogenic activity 1 Less than 8 gamma 50 gamma 125 gamma.

I Weight required to produce estrus in ovariectomized rats.

The methyl, butyl and amyl groups in the ethers shown in the above table are examples oi. alkyls containing 1 to 5 carbon atoms.

To recapitulate, the mon-ethers of hexestrol and other poly-phenols exhibit improved physiological qualities over the parent compounds. Where such parent compounds produce an estrus of passing duration of the order of 2 or 3 days, it is to be noted that the mono-ethers of hexestrol are characterized by the capacity to produce estrus of increased duration. The duration of the estrus may be increased at will by increased doses, and without undue physiological effects, or undesirable manifestations.

H H Q Q- 411E. 3:115 in which R. is an alkyl radical containing 1 to 5 carbon atoms.

FRANZ C. SCI-DWELICES.

CERTIFICATE OF CORRECTIUN Patent No. 2,385, l-72- September 25, 1914.5.

FRANZ c. scmmms.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows: Page 2, first column, line 25, for mon-ethers" read -.-meno-ethers--; and second column,

line 27, claim 1, after "phenyl" insert --hexane-; and that the said Letters Patent should be read with this correction therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 15th day of January, A. D. 19146.

Leslie Frazer (Seal) First Assistant Commissioner of Patents. 

